The objects of this proposal are to establish the limits of metabolic adaptation in ischemic myocardium and to evaluate several interventions designed to improve energy production and (or) mechanical function. We have observed that myocardial ischemia results in accumulation of several inhibitory metabolites. Nevertheless, manipulations which either modify or circumvent these products can be effected to stimulate residual oxidative phosphorylation. Studies in working and arrested swine hearts are planned to continue these investigations. Emphasis will be specifically directed at determining the effects of substrate enhancement, documenting the influence of agents designed to blunt the effects of fatty acid excess, and detailing further the impact of coronary washout. Alternate substrates which may have specific advantages in providing mitochondria with increased supplies of acetyl CoA include: acetate, acetoacetate, beta hydroxybutyrate and pyruvate with dichloroacetate. L, D, and Dl isomers of carnitine will also be evaluated to determine the magnitude and distribution of their intracellular incorporations, the effects of their isomeric stereospecificity, and their mechanisms of action including effects independent of possible influences in modifying certain fatty acid inhibitors. Studies to evaluate the impact of coronary washout on preserving metabolic and mechanical functions, by altering vascular redistributions and washing away critical metabolic inhibitors, are also planned. Finally, studies are proposed to document the metabolic changes which occur with cold cardioplegia and to attempt several interventions designed to enhance energy production during the arrest period and improve long term mechanical recovery. Major emphasis will again be directed at detailing the effects of substrate enhancement, carnitine, and coronary washout with oxygen and buffers on cardiac metabolism and mechanical function. It is hoped that a critical evaluation of cardiac metabolism and energy production during the cold arrest and reperfusion periods will provide added insights to possible therapeutic options for future myocardial protection and better long term recovery.